Abstract
The functional state of the skeletal muscle Ca2+ release channel is modulated by a number of endogenous molecules during excitation-contraction. Using electron cryomicroscopy and angular reconstitution techniques, we determined the three-dimensional (3D) structure of the skeletal muscle Ca2+ release channel activated by a nonhydrolyzable analog of ATP in the presence of Ca2+. These ligands together produce almost maximum activation of the channel and drive the channel population toward a predominately open state. The resulting 30-A 3D reconstruction reveals long-range conformational changes in the cytoplasmic region that might affect the interaction of the Ca2+ release channel with the t-tubule voltage sensor. In addition, a central opening and mass movements, detected in the transmembrane domain of both the Ca(2+)- and the Ca2+/nucleotide-activated channels, suggest a mechanism for channel opening similar to opening-closing of the iris in a camera diaphragm.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenosine Triphosphate / analogs & derivatives*
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Adenosine Triphosphate / pharmacology
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Calcium / metabolism
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Calcium / pharmacology*
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Cryoelectron Microscopy
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Egtazic Acid / pharmacology
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Ion Channel Gating / drug effects*
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Ligands
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Models, Molecular
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Muscle, Skeletal / chemistry*
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Muscle, Skeletal / cytology
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Muscle, Skeletal / drug effects
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Muscle, Skeletal / metabolism
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Protein Conformation
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Ryanodine Receptor Calcium Release Channel / chemistry
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Ryanodine Receptor Calcium Release Channel / metabolism*
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Ryanodine Receptor Calcium Release Channel / ultrastructure*
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Sarcoplasmic Reticulum / chemistry
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Sarcoplasmic Reticulum / drug effects
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Sarcoplasmic Reticulum / metabolism
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Sarcoplasmic Reticulum / ultrastructure
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Structure-Activity Relationship
Substances
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Ligands
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Ryanodine Receptor Calcium Release Channel
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5'-adenylyl (beta,gamma-methylene)diphosphonate
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Egtazic Acid
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Adenosine Triphosphate
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alpha,beta-methyleneadenosine 5'-triphosphate
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Calcium